Skip to main content

Advertisement

SpringerLink
Log in

Phase I study of the mTOR inhibitor everolimus in combination with the histone deacetylase inhibitor panobinostat in patients with advanced clear cell renal cell carcinoma

  • PHASE I STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Background Preclinical studies suggested synergistic anti-tumor activity when pairing mTOR inhibitors with histone deacetylase (HDAC) inhibitors. We completed a phase I, dose-finding trial for the mTOR inhibitor everolimus combined with the HDAC inhibitor panobinostat in advanced clear cell renal cell carcinoma (ccRCC) patients. We additionally investigated expression of microRNA 605 (miR-605) in serum samples obtained from trial participants. Patients and Methods Twenty-one patients completed our single institution, non-randomized, open-label, dose-escalation phase 1 trial. miR-605 levels were measured at cycle 1/day 1 (C1D1) and C2D1. Delta Ct method was utilized to evaluate miR-605 expression using U6B as an endogenous control. Results There were 3 dosing-limiting toxicities (DLTs): grade 4 thrombocytopenia (n = 1), grade 3 thrombocytopenia (n = 1), and grade 3 neutropenia (n = 1). Everolimus 5 mg PO daily and panobinostat 10 mg PO 3 times weekly (weeks 1 and 2) given in 21-day cycles was the recommended phase II dosing based on their maximum tolerated dose. The 6-month progression-free survival was 31% with a median of 4.1 months (95% confidence internal; 2.0–7.1). There was higher baseline expression of miR-605 in patients with progressive disease (PD) vs those with stable disease (SD) (p = 0.0112). PD patients’ miR-605 levels decreased after the 1st cycle (p = 0.0245), whereas SD patients’ miR-605 levels increased (p = 0.0179). Conclusion A safe and tolerable dosing regimen was established for combination everolimus/panobinostat therapy with myelosuppression as the major DLT. This therapeutic pairing did not appear to improve clinical outcomes in our group of patients with advanced ccRCC. There was differential expression of miR-605 that correlated with treatment response. Clinical trial information: NCT01582009.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Motzer RJ, Escudier B, McDermott DF et al (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1803–1813. https://doi.org/10.1056/NEJMoa1510665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Motzer RJ, Hutson TE, Tomczak P et al (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124. https://doi.org/10.1056/NEJMoa065044

    Article  CAS  PubMed  Google Scholar 

  3. Rini BI, Halabi S, Rosenberg JE et al (2008) Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 26:5422–5428. https://doi.org/10.1200/jco.2008.16.9847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Choueiri TK, Escudier B, Powles T et al (2015) Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1814–1823. https://doi.org/10.1056/NEJMoa1510016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Motzer RJ, Tannir NM, McDermott DF et al (2018) Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 378:1277–1290. https://doi.org/10.1056/NEJMoa1712126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Choueiri TK, Halabi S, Sanford BL et al (2017) Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial. J Clin Oncol 35:591–597. https://doi.org/10.1200/JCO.2016.70.7398

    Article  CAS  PubMed  Google Scholar 

  7. Motzer RJ, Escudier B, Oudard S et al (2010) Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 116:4256–4265. https://doi.org/10.1002/cncr.25219

    Article  CAS  PubMed  Google Scholar 

  8. Battelli C, Cho DC (2011) mTOR inhibitors in renal cell carcinoma. Therapy 8:359–367. https://doi.org/10.2217/thy.11.32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Voss MH, Molina AM, Motzer RJ (2011) mTOR inhibitors in advanced renal cell carcinoma. Hematol Oncol Clin North Am 25:835–852. https://doi.org/10.1016/j.hoc.2011.04.008

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lin F, Zhang PL, Yang XJ et al (2006) Morphoproteomic and molecular concomitants of an overexpressed and activated mTOR pathway in renal cell carcinomas. Ann Clin Lab Sci 36:283–293

    CAS  PubMed  Google Scholar 

  11. Motzer RJ, Barrios CH, Kim TM et al (2014) Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol 32:2765–2772. https://doi.org/10.1200/jco.2013.54.6911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bhatt RS, Landis DM, Zimmer M et al (2008) Hypoxia-inducible factor-2α: effect on radiation sensitivity and differential regulation by an mTOR inhibitor. BJU Int 102:358–363. https://doi.org/10.1111/j.1464-410X.2008.07558.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101. https://doi.org/10.1126/science.1106148

    Article  CAS  PubMed  Google Scholar 

  14. Wang XF, Qian DZ, Ren M et al (2005) Epigenetic modulation of retinoic acid receptor β2 by the histone deacetylase inhibitor MS-275 in human renal cell carcinoma. Clin Cancer Res 11:3535–3542. https://doi.org/10.1158/1078-0432.CCR-04-1092

    Article  CAS  PubMed  Google Scholar 

  15. Fritzsche FR, Weichert W, Röske A et al (2008) Class I histone deacetylases 1, 2 and 3 are highly expressed in renal cell cancer. BMC Cancer 8:381. https://doi.org/10.1186/1471-2407-8-381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kanao K, Mikami S, Mizuno R et al (2008) Decreased acetylation of histone H3 in renal cell carcinoma: a potential target of histone deacetylase inhibitors. J Urol 180:1131–1136. https://doi.org/10.1016/j.juro.2008.04.136

    Article  CAS  PubMed  Google Scholar 

  17. Hainsworth JD, Infante JR, Spigel DR et al (2011) A phase II trial of panobinostat, a histone deacetylase inhibitor, in the treatment of patients with refractory metastatic renal cell carcinoma. Cancer Investig 29:451–455. https://doi.org/10.3109/07357907.2011.590568

    Article  CAS  Google Scholar 

  18. Chen S, Sang N (2011) Histone deacetylase inhibitors: the epigenetic therapeutics that repress hypoxia-inducible factors. J Biomed Biotechnol 2011:197946. https://doi.org/10.1155/2011/197946

    Article  CAS  PubMed  Google Scholar 

  19. Fath DM, Kong X, Liang D et al (2006) Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-α. J Biol Chem 281:13612–13619. https://doi.org/10.1074/jbc.M600456200

    Article  CAS  PubMed  Google Scholar 

  20. Andreu-Vieyra CV, Berenson JR (2014) The potential of panobinostat as a treatment option in patients with relapsed and refractory multiple myeloma. Ther Adv Hematol 5:197–210. https://doi.org/10.1177/2040620714552614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Verheul HMW, Salumbides B, Van Erp K et al (2008) Combination strategy targeting the hypoxia inducible factor-1 α with mammalian target of rapamycin and histone deacetylase inhibitors. Clin Cancer Res 14:3589–3597. https://doi.org/10.1158/1078-0432.CCR-07-4306

    Article  CAS  PubMed  Google Scholar 

  22. San-Miguel JF, Hungria VTM, Yoon SS et al (2014) Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 15:1195–1206. https://doi.org/10.1016/S1470-2045(14)70440-1

    Article  CAS  PubMed  Google Scholar 

  23. Jansson MD, Lund AH (2012) MicroRNA and cancer. Mol Oncol 6:590–610. https://doi.org/10.1016/j.molonc.2012.09.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Xiao J, Lin H, Luo X et al (2011) miR-605 joins p53 network to form a p53:miR-605:Mdm2 positive feedback loop in response to stress. EMBO J 30:524–532. https://doi.org/10.1038/emboj.2010.347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Li J, Tian F, Li D et al (2014) MiR-605 represses PSMD10/Gankyrin and inhibits intrahepatic cholangiocarcinoma cell progression. FEBS Lett 588:3491–3500. https://doi.org/10.1016/j.febslet.2014.08.008

    Article  CAS  PubMed  Google Scholar 

  26. Zhou YJ, Yang HQ, Xia W et al (2017) Down-regulation of miR-605 promotes the proliferation and invasion of prostate cancer cells by up-regulating EN2. Life Sci 190:7–14. https://doi.org/10.1016/j.lfs.2017.09.028

    Article  CAS  PubMed  Google Scholar 

  27. Miao L, Wang L, Zhu L et al (2016) Association of microRNA polymorphisms with the risk of head and neck squamous cell carcinoma in a Chinese population: a case-control study. Chin J Cancer 35:77. https://doi.org/10.1186/s40880-016-0136-9

    Article  PubMed  PubMed Central  Google Scholar 

  28. Zibelman M, Wong YN, Devarajan K et al (2015) Phase I study of the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat in advanced renal cell carcinoma and other solid tumors. Investig New Drugs 33:1040–1047. https://doi.org/10.1007/s10637-015-0261-3

    Article  CAS  Google Scholar 

  29. Tabernero J, Rojo F, Calvo E et al (2008) Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 26:1603–1610. https://doi.org/10.1200/JCO.2007.14.5482

    Article  CAS  PubMed  Google Scholar 

  30. Pili R, Liu G, Chintala S et al (2017) Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in patients with clear-cell renal cell carcinoma: a multicentre, single-arm phase I/II clinical trial. Br J Cancer 116:874–883. https://doi.org/10.1038/bjc.2017.33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Aggarwal R, Thomas S, Pawlowska N et al (2017) Inhibiting histone deacetylase as a means to reverse resistance to angiogenesis inhibitors: phase I study of abexinostat plus pazopanib in advanced solid tumor malignancies. J Clin Oncol 35:1231–1239. https://doi.org/10.1200/JCO.2016.70.5350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pili R, Quinn DI, Hammers HJ et al (2017) Immunomodulation by entinostat in renal cell carcinoma patients receiving high-dose interleukin 2: a multicenter, single-arm, phase I/II trial (NCI-CTEP#7870). Clin Cancer Res 23:7199–7208. https://doi.org/10.1158/1078-0432.CCR-17-1178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Orillion A, Hashimoto A, Damayanti N et al (2017) Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma. Clin Cancer Res 23:5187–5201. https://doi.org/10.1158/1078-0432.CCR-17-0741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Motzer RJ, Hutson TE, Glen H et al (2015) Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol 16:1473–1482. https://doi.org/10.1016/S1470-2045(15)00290-9

    Article  CAS  PubMed  Google Scholar 

  35. Morales S, De Mayo T, Gulppi FA et al (2018) Genetic variants in pre-miR-146a, pre-miR-499, pre-miR-125a, pre-miR-605, and pri-miR-182 are associated with breast cancer susceptibility in a south American population. Genes (Basel) 9. https://doi.org/10.3390/genes9090427

  36. Moazeni-Roodi A, Ghavami S, Hashemi M (2019) Lack of association between miR-605 rs2043556 polymorphism and overall cancer risk: a meta-analysis of case-control studies. Microrna 8:94–100. https://doi.org/10.2174/2211536608666181204110508

    Article  CAS  PubMed  Google Scholar 

  37. Wang S, Zhu H, Ding B et al (2019) Genetic variants in microRNAs are associated with cervical cancer risk. Mutagenesis 34:127–133. https://doi.org/10.1093/mutage/gez005

    Article  CAS  PubMed  Google Scholar 

  38. Hu M, Yu Z, Luo D et al (2018) Association between the polymorphism in miR-605 and cancer susceptibility: a PRISMA-compliant meta-analysis. Clin Lab 64. https://doi.org/10.7754/Clin.Lab.2018.180545

  39. Miller M, Shirole N, Tian R et al (2016) The evolution of TP53 mutations: from loss-of-function to separation-of-function mutants. J Cancer Biol Res 4(4)

  40. Id Said B, Malkin D (2015) A functional variant in miR-605 modifies the age of onset in Li-Fraumeni syndrome. Cancer Genet 208:47–51. https://doi.org/10.1016/j.cancergen.2014.12.003

    Article  CAS  PubMed  Google Scholar 

  41. Lawson J, Dickman C, MacLellan S et al (2017) Selective secretion of microRNAs from lung cancer cells via extracellular vesicles promotes CAMK1D-mediated tube formation in endothelial cells. Oncotarget 8:83913–83924. https://doi.org/10.18632/oncotarget.19996

    Article  PubMed  PubMed Central  Google Scholar 

  42. Gendarme M, Baumann J, Ignashkova TI et al (2017) Image-based drug screen identifies HDAC inhibitors as novel golgi disruptors synergizing with JQ1. Mol Biol Cell 28:3756–3772. https://doi.org/10.1091/mbc.E17-03-0176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The clinical trial was supported in part by an unrestricted grant from Novartis Pharmaceuticals. The funder had no role in collection and interpretation of data and writing of the report.

Author information

Authors and Affiliations

  1. Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, 535 Barnhill Drive, RT 400, Indianapolis, IN, 46202, USA

    Anthony Wood, Nabil Adra, Sreenivasulu Chintala, Nur Damayanti & Roberto Pili

  2. Roswell Park Comprehensive Cancer Center, 665 Elm St, Buffalo, NY, 14203, USA

    Saby George

Authors
  1. Anthony Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Saby George
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nabil Adra
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sreenivasulu Chintala
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nur Damayanti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Roberto Pili
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roberto Pili.

Ethics declarations

Conflict of interest

Anthony Wood declares that he has no conflict of interest. Saby George declares that he has no conflict of interest. Nabil Adra declares that he has no conflict of interest. Sreenivasulu Chintala declares that he has no conflict of interest. Nur Damayanti declares that she has no conflict of interest. Roberto Pili declares that he has no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wood, A., George, S., Adra, N. et al. Phase I study of the mTOR inhibitor everolimus in combination with the histone deacetylase inhibitor panobinostat in patients with advanced clear cell renal cell carcinoma. Invest New Drugs 38, 1108–1116 (2020). https://doi.org/10.1007/s10637-019-00864-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-019-00864-7

Keywords

Search

Navigation